Improved process for the preparation of rivaroxaban involving novel intermediate

ABSTRACT

The present invention relates to the novel key intermediate, 4-{4-[(5 S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one perchlorate, in the synthesis of rivaroxaban. The invention further relates to the crystalline form of novel intermediate, the process to prepare the novel intermediate and method of preparing rivaroxaban using this novel intermediate. The invention provides an improved and efficient process for preparation of Rivaroxaban.

TECHNICAL FIELD

The present invention provides novel intermediate, process to preparenovel intermediate and an efficient and improved process for preparationof Rivaroxaban or its pharmaceutically acceptable salt using novelintermediate.

BACKGROUND OF THE INVENTION

Rivaroxaban chemically known as(S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide (FORMULA-1), isan oral anticoagulant and is marketed under brand name Xarelto. It isthe first available orally active direct factor Xa inhibitor. On Jul. 1,2011, the U.S. Food and Drug Administration (FDA) approved Rivaroxabanfor prophylaxis of deep vein thrombosis (DVT), which may lead topulmonary embolism (PE), in adults undergoing hip and knee replacementsurgery. On Nov. 4, 2011, the U.S. FDA approved rivaroxaban for strokeprophylaxis in people with non-valvular atrial fibrillation.

A process for the preparation of the Rivaroxaban and its intermediatewas first disclosed in WO2001047919 (U.S. Pat. No. 7,157,456 B2) asshown in Scheme I, which includes: i. Reaction between I with aq.Methylamine in ethanol to produce 4-[{4-[(5S)-5-(-Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}]-morpholin-3-one(Oxazolidine amine II);

ii. Further condensation of 4-[{4-[(5S)-5-(-Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}]-morpholin-3-one(Oxazolidine amine II) with 5-chlorothiophene-2-carbonyl chloride inpyridine to produce(S)-5-chloro-N{[2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-2-yl]methyl}thiophene-2-carboxamide (Rivaroxaban of FORMULA-1). In this process allintermediates and final API are purified using flash chromatography.Moreover use of excess dichloromethane and pyridine as a solvent limitsits commercial scale production due to handling difficulties.

Similar process is disclosed in Journal of medicinal chemistry, 2005,48, 5900-5908. U.S. Pat. No. 7,351,823 discloses a process to preparerivaroxaban by slightly modifying the process disclosed in U.S. Pat. No.7,157,456 to get the better yield of the product as compared to U.S.Pat. No. 7,157,456. However the yields of U.S. Pat. No. 7,157,456 stillprovide the scope for improvement. In the said process, intermediate VIin scheme I is converted into its hydrochloride salt and then reactedwith 5-chlorothiophene-2-carbonyl chloride to get Rivaroxaban. Thepatent however does not mention the purity of the final product. Dimericimpurities are formed in the process disclosed in U.S. Pat. No.7,351,823.

On the similar lines as that of U.S. Pat. No. 7,351,823, many processesfor preparation of rivaroxaban have been claimed and disclosed in thepatents thereafter, wherein the step of converting compound VI in schemeI to Rivaroxaban is modified.

Either different salts of compound VI have been prepared or the baseused in the reaction is changed or the solvents are selected in such away that the yield, ease of handling and the affordability of thereaction of the overall process improves. U.S. Pat. No. 8,188,270 claimsnovel modifications and solvates of rivaroxaban and in Example 2. Thepatent discloses the process to prepare rivaroxaban in which compound VIas HCl salt is reacted with 5-chlorothiophene-2-carbonyl chloride inpresence of triethyl amine and N-methyl-2-pyrrolidone (NMP) as solvent.Use of NMP in larger amount on industrial scale is undesirable, highlydangerous and environmentally unfriendly.

US2013253187 discloses a process to prepare rivaroxaban by reactingcompound VI as its salt (preferably sulphate) with5-chlorothiophene-2-carbonyl chloride in presence of organic base havingpKa higher than 5.3, or mixtures thereof. Particularly preferred organicbases are organic bases with a pKa higher than 8.5, more preferablyorganic bases with a pKa higher than 10.0. The most preferred base beingN,N-diisopropyl ethylamine (DIPEA). The application further mentionsthat, ‘the use of an organic base instead of an inorganic base givesmore versatility to the reaction’ and ‘the organic base easily dissolvesin both organic media and water, which provides a more effectivereaction and therefore better yield’. Use of excess of costly CDI,elaborate purification to separate byproducts from desired product andextensive purification process of two crystallizations to obtain pureRivaroxaban compromises yields and makes the process lengthy andundesirable.

WO2013053739 provides a process to prepare rivaroxaban using compoundVI, wherein compound VI is in its acid addition salt form and whereinthe acid is specifically an organic acid. The drawback of the processare the extremely low yields (65-85%) of acid addition salts andconversion of acid addition salt to crude rivaroxaban gives product innot more than 90% yield. Further purification of this low yielded cruderivaroxaban decreases the yield of final pure rivaroxaban.

In WO2013120465 the process used in the preparation of acid additionsalt of compound VI is:

wherein HA stands for an acid selected from the group ofmethanesulfonic, benzenesulfonic, p-toluenesulfonic, (R)— and (S)—camphorsulfonic, hydrochloric, hydrobromic, phosphoric, nitric,sulphuric, D- and L- tartaric, benzoic, oxalic and trifluoroacetic acid.Use of unstable reagents such as aldehyde and imine, lower carbonefficiency, lengthy process to prepare Rivaroxaban via imine areundesirable features of the process. Also low yield of 51% in imineformation and 68% in coupling of imine with amino morpholine derivative,drastically reduces the overall yield of the process. Use costly &pyrophoric t-BuOLi makes process unsafe on larger scales and costly.

WO2013098833 provides compounds of formula VI in various inorganic andorganic salt forms and their solid state forms. It claims a process toprepare rivaroxaban using these salts and rivaroxaban with high purity.The process uses sulphonyl halides to prepare rivaroxaban which arepotential source of genotoxic impurity after reacting with alcoholicsolvent. A process claimed by WO2015198259 uses Nitrate salt of compoundVI and the overall yield of rivaroxaban is low.

It has been observed that plain base or an amine when treated with5-chlorothiophene-2-carbonyl chloride leads to formation of Rivaroxabanwith extremely poorer yields. It was also observed that when a salt ofthe amine is used for reaction with 5-chlorothiophene-2-carbonylchloride, better yields and purity are obtained. It is also noticed thatdifferent salts give different purity and yield for the reaction. Itmakes it very clear that the amine is different from its salts in manyaspects, primarily salts are significantly different from each other andfrom the amine from which they are formed. Different salts behavedifferently in the reaction. Stability and reactivity or the ability ofdifferent salts of amine to form quality of rivaroxaban isunpredictable. Therefore salts are not same as the amine from which theyare formed.

In view of the drawbacks associated with prior art processes, there is aneed to provide a better, highly energy efficient, cheap, safe processwithout the use of corrosive and pyrophoric chemicals, to preparerivaroxaban which is suitable for industrial scale ups and whichproduces all the intermediates and the final product substantially freeof impurities and in high yields.

OBJECT OF THE INVENTION

The main object of the present invention is to provide a process toprepare rivaroxaban using novel key intermediate, wherein the process ishighly energy efficient, cheap, safe and easily scalable.

Another object of the invention is to provide novel key intermediates inthe synthesis of rivaroxaban, which are high yielding, easily purifiedand easy to handle.

Yet another object of the invention is to provide a process to preparekey intermediate in the synthesis of rivaroxaban wherein the process ishigh yielding and easy to carry out on larger scale.

Yet another object of the invention is to provide highly purecrystalline form of the key intermediate in the synthesis ofrivaroxaban.

Yet another object of the invention is provide a process to prepare acrystalline form of the key intermediate in the synthesis ofrivaroxaban.

SUMMARY OF THE INVENTION

The present invention provides a process to prepare Rivaroxaban using4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) as a novel key intermediate.

The present invention further provides a novel intermediate 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5).

The present invention provides a process to prepare 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5), wherein the process comprises:

i. reacting 2-{(5S)-2-oxo-3-[(4-(3-oxo-4-morpholynyl)phenyl]-1,3-oxazolidine-5-yl}methyl-1H-isoindole-1,3 (2H)-dione of Formula-4 with methylamine to obtain amine of Formula-4ain-situ;

ii. converting in-situ prepared amine of Formula-4a in step i to4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5 by reacting it with Perchloric acid;

In the present invention there is provided a crystalline 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5).

As per one more aspect of the present invention there is provided aprocess to prepare highly pure, crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5, wherein the process comprises the steps of:

i. Crystallization of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-oxazolidin-3-]-phenyl}-morpholin-3-oneperchlorate using solvent selected form methanol IPA, Ethanol,Dichloromethane or mixture thereof at a temperature of 30° C.-82° C.;

ii. Separation of crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate from the solvent.

There is also provided a process to prepare rivaroxaban usingcrystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5), wherein the process comprises:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: XRPD pattern of crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) Peak List: List of Peaks as depicted in FIG. 1

FIG. 2: Differential scanning calorimetry of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5)

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process to prepare Rivaroxaban using4-{4-[(5S)-5-(Aminomethyl)-2-oxo-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of formula-5 as a novel key intermediate, wherein theprocess comprises:

i. reacting 2-{(5S)-2-oxo-3-[(4-(3-oxo-4-morpholynyl)phenyl]-1,3-oxazolidine-5-yl}methyl-1H-isoindole-1,3(2H)-dioneof Formula-4 with aqueous methylamine to obtain amine of Formula-4ain-situ;

ii. converting in-situ prepared amine of Formula 4a in step i to4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5 by reacting it with Perchloric acid;

iii. reacting 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5, obtained in step ii with5-chlorothiophene-2-carbonyl chloride in presence of a base and solventto obtain Rivaroxaban of Formula-1.

The compound of the Formula-4 is prepared by the processes known in theprior art. The reaction in step i is carried out using excess of aqueousmethylamine in presence of solvent selected from methanol, ethanol,isopropyl alcohol (IPA), water or mixture thereof; preferably IPA, attemperature from 30° C. to 60° C. preferably at 45° C. to 50° C. Thein-situ prepared amine in step i is acidified using perchloric acid inthe same solvent as that in step i to produce 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5.

4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5 formed in step ii is in crystalline form.Formula-5 in its crystalline form is used as a starting material in thesynthesis of rivaroxaban in step iii.

The reaction between perchlorate of Formula-5 with5-chlorothiophene-2-carbonyl chloride as in step iii is carried out inpresence of an inorganic base selected from Sodium bicarbonate, Sodiumcarbonate, Potassium bicarbonate, Potassium carbonate, Lithiumcarbonate, or an organic base selected from Triethylamine, N,Ndiisopropylethyl amine, Pyridine; preferably Sodium carbonate in asolvent selected from ketones such as Acetone, Methyl ethyl ketone,N-methylpyroolidone, Methyl isobutyl ketone (MIBK), aromatichydrocarbons such as Toluene, Xylene, chlorinated solvents such asDichloromethane, Chloroform, Chlorobenzene, esters such as Ethylacetate, Methyl acetate, amides such as Dimethylformamide,Dimethylacetamide, or solvents selected from Acetonitrile, water,Dimethyl sulfoxide, ethers such as Tetrahydrofuran, Dioxane, andmixtures thereof, preferably in mixture of Acetone, Toluene and water,in the ratio of 2.4:2.2:5.17.

Final yield of Rivaroxaban was upto 98%. The purity of final product wasas per ICH standards. The process of the present invention was highyielding as compared to processes in the prior art. Raw materials usedin the process were cheap and easy to handle, thus making the processcost effective, energy efficient and highly efficient.

Use of perchloric acid to form 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate is normally unheard of. The reason may be that theperchloric acid per se is highly reactive and has strong oxidizingeffect. The reason may be the fact that perchloric acid being a verystrong oxidizing agent and oxidizes the compound very fast, the momentit comes into contact with it. As a result an effort to form a salt withperchloric acid may result into unstable salt and would foul the purposeof preparing a perchloric acid salt.

However, surprisingly it was noticed that 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate is stable, highly pure, crystalline and is produced in verygood yields.

Unlike the salts used in the prior art, perchlorate salt was found to behigh yielding making the process efficient, easy to handle thereforeeasily scalable and could be prepared in situ in reaction mixture duringamine preparation. It also gives highly pure product, both the salt aswell as rivaroxaban in the next step. Use of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) of Formula-5 as a key intermediate in thesynthesis of rivaroxaban makes the entire process cost effective, energyefficient and easily scalable.

US2013253187 states that the use of organic base in the reaction betweensulphate of 4-{4-[(5 S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one and 5-chlorothiophene-2-carbonyl chloride, provides amore effective reaction and therefore better yield. Surprisingly it wasnoticed that, Sodium carbonate, an inorganic base, made this reactionhigh yielding, easy to handle and highly efficient. Also the cost ofinorganic base as compared to DIPEA, used in US 2013253187 isconsiderably less, making process cheaper. The yields of reaction inpresent invention are better than those of US 2013253187. Also the timerequired in the present invention to prepare rivaroxaban is lesser thanthat disclosed in US2013253187. Use of inorganic bases makes the processuser friendly and nature friendly. As per one aspect of the invention,there is provided 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl }-morpholin-3-oneperchlorate (Formula-5).

It was surprisingly found that as compared to other known salts of4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one,the yield of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) was high and the product obtained was in highlypure form. Surprisingly it was noticed that although perchloric acid isa strong oxidizing agent, use of perchloric acid could yield a stablesalt. The salt was easy to handle and easily scalable. The yield of4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate was higher than that of widely used hydrochloric acid saltmentioned in prior art U.S. Pat. No. 7,351,823.

In another aspect of the invention, there is provided a process toprepare 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5), wherein the process comprises;

i. reacting 2-{(5S)-2-oxo-3-[(4-(3-oxo-4-morpholynyl)phenyl]-1,3-oxazolidine-5-yl}methyl-1H-isoindole-1,3(2H)-dioneof Formula-4 with methylamine to obtain amine of Formula-4a in-situ;

ii. converting in-situ prepared amine of Formula-4a in step i to4-{4-[(5 S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one perchlorate of Formula-5 by reacting it withPerchloric acid;

The reaction in step i is carried out using excess of aqueousmethylamine in presence of solvent selected from methanol, ethanol, IPAwater or mixture thereof; preferably IPA, at temperature from 30° C. to60° C. preferably at 45° C. to 50° C. The in-situ obtained amine isacidified using perchloric acid to produce 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5.

In another aspect of the invention there is provided a highly purecrystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5).

Crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) is characterized by XRPD pattern with 2θ valuesat 10.26, 19.27, 20.24, 20.58, 24.04 and 31.09 +/−0.2θ.

Crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) is characterized by XRPD pattern with 2θ valuesat 10.26, 13.70, 19.67, 20.37, 23.08, 24.76 +/−0.2θ.

Crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}morpholin-3-oneperchlorate (Formula-5) is characterized by XRPD pattern with 2θ valuesat 13.70, 19.27, 20.24, 20.37, 24.04 +/−0.2θ.

Accordingly, crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) is characterized by XRPD pattern with 2θ valuesat 10.26, 13.70, 19.27, 19.67, 20.24, 20.37, 20.58, 23.08, 24.04, 24.76and 31.09 +/−0.2θ.

The crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) is further characterized by the XRPD patternwith 2θ values at 12.81, 13.17, 14.31, 14.58, 16.84, 18.94, 21.25,21.39, 21.88, 22.33, 23.75, 27.58, 28.88, 29.06, 29.57, 30.59, +/−0.2θ.

The crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) is characterized by the XRPD pattern as shown inFIG. 1.

The crystalline form is further characterized by DSC. The product showedDSC endotherm at 206.84° C. as shown in FIG. 2.

A compound is said to be in highly pure form, when the purity of thecompound is measured by HPLC and gives value of more than 99%.

As per one aspect of the invention there is provided a process toprepare highly pure crystalline form of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl }-morpholin-3-oneperchlorate (Formula-5), wherein the process comprises the steps of:

i. reacting 2-{(5S)-2-oxo-3-[(4-(3-oxo-4-morpholynyl)phenyl}-1,3-oxazolidine-5-yl]methyl-1H-isoindole-1,3(2H)-dioneof Formula-4 with methylamine to obtain amine of Formula-4a in-situ;

ii. converting in-situ prepared amine of Formula-4a in step i to4-{4-[(5 S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one perchlorate of Formula-5 by reacting it withPerchloric acid;

iii. crystallizing 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5 obtained in step ii in a solvent selected fromAcetic acid, methanol, IPA, ethanol, Dichloromethane and mixture thereofat a temperature of 30° C. to 82° C. to obtain crystals of 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula 5.

iv. Separating crystal of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate from the solvent.

The reaction in step i is carried out using excess of aqueousmethylamine in presence of solvent selected from methanol, ethanol, IPAwater or mixture thereof; preferably IPA, at temperature from 30° C. to60° C. preferably at 45° C. to 50° C. The amine obtained in step i isacidified using perchloric acid to produce 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5.

Crystallization of 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate is carried out using solvent selected from acetic acid,methanol, IPA, ethanol, dichloromethane or mixture thereof; preferablyin the mixture of dichloromethane and methanol in the ratio of 1:3 to3:1, preferred being 4:2, at a temperature of 30° C. to 82° C. Thecrystals of Formula-5 were separated by Filtration.

As described earlier, the very nature of perchloric acid discourages itsuse to form a salt for use in the reactions. Surprisingly the crystalform of Formula 5 was found to be stable, and was produced in very goodyields with excellent purity. The deprotection reaction was carried outin Isopropyl alcohol. When the perchloric acid was added to the reactionmass 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula 5 separated out from the reaction mass.

Surprisingly, the accidentally obtained crystalline 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula 5 is obtained in high yield (94%) and in highlypure form. This negated the necessity to purify intermediates separatelyand therefore made the process cost effective, easy to perform,industrially scalable and environment friendly. This also gave the purerivaroxaban in high yield and purity.

The very fact that use of perchlorate i.e. 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate results into better yields and better purity of Rivaroxabanthan use of mere 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-onemeans the two are not same and cannot be presumed to be same.

These two are technically, structurally and constitutionally dissimilarand are not superimposable. They significantly differ in theirperformance in reaction dynamics because of inherent differences in themwhich result into differential yields and purity of the product.

The below given examples demonstrate best mode of carrying out thepresent invention and do not limit invention in any manner.

EXAMPLES Example-1 Preparation of 2-(2R)-hydroxy-3-{[4-(3-oxo-4-morphonyl)phenylamino]propyl}-1H-isoindole-1,3(2H)-dione(Formula-3) from 4-(4-aminophenyl)morpholinone (Formula-2) and(S)-(+)glycidyl phthalimide

4-(4-aminophenyl)morpholinone 100 gm, 0.5202 moles and (S)-(+)glycidylphthalimide 106.6 gm (0.5246 moles) was charged to the mixture of,methanol and water 1000 ml (9:1) and heated to 65° C.-70° C. Continuedstirring for next 20 hrs at 65° C.-70° C. Add second lot ofS)-(+)glycidyl phthalimide 10.6 gm (0.05246 moles) and 200 ml (9:1)methanol water mixture and stir for next 12 hrs. Cooled the reactionmass to 25° C.-30° C. and filter the slurry on Buckner funnel, suckdried well. Wet cake washed with 100 ml mixture of methanol and water(9:1). The solid obtained was dried at 50° C. to 55° C. to get 190 gmcompound of Formula-3 as dry material. Yield-92%

Example-2 Preparation of 2-{(5S)-2-oxo-3-[4-(3-oxo-4-morpholynyl)phenyl]-1,3-oxazolidine-5-yl}methyl-1H-isoindole-1,3(2H)-dione (Formula-4) from 2-(2R)-hydroxy-3-{[4-(3-oxo-4-morphonyl)phenylamino]propyl}-1H-isoindole-1,3(2H)-dione(Formula-3)

Amino alcohol 170 gm, 0.4293 moles and Triethylamine 4114.72 gms, 0.9459moles, was charged to Dichloromethane 2380 ml and cooled reaction massto 0° C.-5° C. To the cooled reaction mass added triphosgene solution,51.09 gms in 340 ml MDC, 0.18 moles drop wise at 5° C.-10° C. in 60 min,and stirred for 60-90 min. Reaction mass quenched with water anddistilled out MDC layer atmospherically till thick solid mass obtained.To the thick solid, charged tetrahydrofuran 1360 ml, distilled out 130ml under vacuum. Cooled slurred mass to 25° C.-30° C., stirred for 30min, filtered. Wet material dried at 55° C.-60° C. to afford 162 gm drymaterial. Yield-89%

Example-3 Preparation of4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) and its crystalline form from 2-{(5S)-2-oxo-3-[4-(3-oxo-4-morpholynyl)phenyl]-1,3-oxazolidine-5-yl}methyl-1H-isoindole-1,3(2H)-dione (Formula-4)

To the slurry of Formula-4 160 gm, 0.379 moles in 800 ml Isopropylalcohol, Charged 40% methylamine solution130 gm, 1.677 moles. Reactionmass was heated up to 45° C.-50° C. for 2-3 Hrs. Distilled out IPA undervacuum and charged fresh 800 ml Isopropyl alcohol Cooled reaction massto 45° C.-50° C. and added 70% solution of Perchloric acid 59.6 gm,0.415 moles. Stirred reaction mass for 1 Hrs at 45-50° C. Cooledreaction mass to 0-5° C., filtered and dried at 50° C.-55° C. to afford160 gm crude 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate. The crude 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate has a crystalline nature and is in considerably pure form.

Preparation of pure crystalline 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) from crude

To Above crude 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate charged 640 ml Dichloromethane (4 vol of starting material)and charged 320 ml methanol. Heated the slurry to 38° C.-40° C. andstirred for 30 min. Cooled the slurry to 20° C. Filtered and suck dried.Product obtained after drying was 138.7 gm pure crystalline perchloratesalt having purity more than 99.5% (Yield-94%)

Example-4 Preparation of Rivaroxaban from4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5)

To the chilled solution of sodium carbonate 5.83 gm, 0.55 moles in 51 mlwater, charged 10 gms, (0.0255 moles) of compound of Formula-5 followedby acetone 24 ml. Stirred for 10 min., Meanwhile prepared dil. solutionof 5-chlorothiophene-2-carbonyl chloride (5.7 gm Chloro compound dilutedwith 22 ml of toluene). Toluene solution of 5-chlorothiophene-2-carbonylchloride was added drop wise at 0° C.-5° C., to the reaction mass. Whitesolid separated out during addition of Toluene solution. Stirred fornext 30 min at 0° C.-5° C., raised the temperature of reaction mass to50° C. and charged 35 ml acetone. Stirred for 30 min at 45° C. to 50°C., followed by cooling and filtration, wet cake was slurred in water at55° C.-60° C. to afford 10.9 gms dry product (Yield-98%).

Above material was purified using methanol Dichloromethane mixturefollowed by acetic acid to afford pure material having HPLC purity 99.8%chiral purity-99.95%.

1. A process to prepare rivaroxaban using 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5), wherein the process comprises: i. reacting2-{(5S)-2-oxo-3-[(4(3-oxo-4-morpholynyl)phenyl]-1,3-oxazolidine-5-yl}methyl-1H-isoindole-1,3(2H)-dioneof Formula-4 with aqueous methylamine to obtain amine of Formula-4ain-situ;

ii. converting in-situ prepared amine of Formula 4a in step i to4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5 by reacting it with Perchloric acid;

iii. reacting 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5, obtained in step ii with5-chlorothiophene-2-carbonyl chloride in presence of a base and solventto obtain Rivaroxaban of Formula-1.


2. The process as claimed in claim 1, wherein a solvent in step i and iiis selected from methanol, ethanol, IPA water or mixture thereof.
 3. Theprocess as claimed in claim 1, wherein the base used in step iii isselected from an inorganic base selected from Sodium bicarbonate, Sodiumcarbonate, Potassium bicarbonate, Potassium carbonate, Lithiumcarbonate, or an organic base selected from Triethylamine, N,Ndiisopropylethyl amine, Pyridine.
 4. The process as claimed in claim 1,wherein the solvent used in step iii is selected from ketones such asAcetone, Methyl ethyl ketone, N-methylpyroolidone, MIBK, aromatichydrocarbons such as Toluene, Xylene, chlorinated solvents such asDichloromethane, Chloroform, Chlorobenzene, esters such as Ethylacetate, Methyl acetate, amides such as Dimethylformamide,Dimethylacetamide, or solvents selected from Acetonitrile, water,Dimethyl sulfoxide, ethers such as Tetrahydrofuran, Dioxane, andmixtures thereof.
 5. The process as claimed in claim 4, wherein themixture of acetone, toluene and water is in the ratio of 2.4:2.2:5.17.6. The process as claimed in claim 1, wherein 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) formed in step ii is in crystalline form. 7.4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5.
 8. A process to prepare 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5) wherein the process comprises; i. reacting 2-{(5S)-2-oxo-3-[(4-(3-oxo-4-morpholynyl)phenyl]-1,3-oxazolidine-5-yl}methyl-1H-isoindole-1,3(2H)-dioneof Formula-4 with methylamine to obtain amine of Formula-4a in-situ;

ii. converting in-situ prepared amine of Formula-4a in step i to4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5 by reacting it with Perchloric acid;


9. The process as claimed in claim 8, wherein a solvent in step i and iiis selected from methanol, ethanol, IPA water or mixture thereof
 10. Acrystalline 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate.
 11. (canceled)
 12. The Crystalline 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate as claimed in claim 10, wherein crystalline 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate is characterized by DSC peak at 206.84° C.
 13. A process toprepare highly pure, crystalline 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate (Formula-5), wherein the process comprises the steps of: i.crystallizing 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate in a crystallizing solvent at a temperature of 30° C. to 82°C.; ii. Separating crystals of 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate from the crystallizing solvent.
 14. The process as claimedin claim 13, wherein in step i crystallizing solvent is selected formAcetic acid methanol, IPA, ethanol, dichloromethane and mixture thereof,preferably mixture of Dichloromethane and methanol in the ratio of 1:3to 3:1, preferred being 4:2.
 15. The process as claimed in claim 13,wherein preferred temperature of crystallization in step i is 30° C. to40° C.
 16. The process as claimed in claim 13, wherein 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate in step i is prepared by the process as claimed in claim 8.17. (canceled)
 18. The Crystalline 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate as claimed in claim 10, wherein crystalline 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate is characterized by XRPD pattern with 2θ values at 10.26,13.70, 19.67, 20.37, 23.08, 24.76 +/−0.2θ.
 19. (canceled) 20.Rivaroxaban as prepared by the process claimed in claim
 1. 21.Rivaroxaban prepared by the process comprising 4-{4-[(5S)-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-oneperchlorate of Formula-5 as an intermediate.